Hereditary Angiodema (HAE)
Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic condition resulting from the over-production of bradykinin. HAE is a disease of the immune system that is caused by a genetic deficiency in C1 inhibitor, a key regulator of several inflammatory pathways, and afflicts approximately one out of 40,000 people globally. In the absence of functional C1 inhibitor, plasma kallikrein is hyperactivated, which results in the production of excess bradykinin, a potent vasodilator and the main mediator of angioedema. The over-production of bradykinin results in episodic swellings that can affect any part of the body, including the abdomen, face, and larynx. These swellings may occur up to 1-2 times per week and may be life-threatening.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Paroxysmal Nocturnal Hemoglobinuria (PNH) is an ultra-rare and life-threatening disease resulting from the chronic hemolysis of a patient’s red blood cells (RBCs). PNH afflicts 1-2 people per million globally. A PNH patient’s immune system attacks their own RBCs because these cells lacks a key inhibitory protein that is normally found on their surface. This inhibitory protein prevents complement attack in healthy individuals. The chronic hemolysis that results causes serious health problems, including blood clots, organ failure, and death.
Complement Pathway Inhibition
Attune Pharmaceuticals has discovered novel small molecule inhibitors of a key component of the complement system. The complement system is an important part of the innate immune system and is comprised of a group of serum proteins that are activated through sequential protease based steps. There are three major pathways of complement activation; the classical, the alternative, and the lectin.
In certain diseases, activation of the complement system results in pathogenesis. For example, in hereditary angioedema (HAE), patients are deficient in C1-INH (C1-inhibitor). The absence of this key inhibitor results in hyperactivation of the classical complement pathway. When activated, high molecular weight kininogen is cleaved by plasma kallikrein, releasing high levels of bradykinin, which causes edema. Attune Pharmaceuticals is advancing oral small molecules inhibitors of plasma kallikrein, which will restore normal levels of bradykinin, potentially preventing or reducing the frequency of HAE attacks.
In the case of paroxysmal nocturnal hemoglobinuria (PNH), a hemolytic anemia, patients are deficient in CD59 (MAC-inhibitory protein) on their red blood cells. CD59 protects these cells from complement-mediated lysis by the membrane attack complex (MAC). In the absence of CD59, the MAC is no longer impeded and attacks the red blood cells when it detects C3b on their surface. While detection of C3b on microbes is a central feature of the alternative pathway, detection on host cells results in pathogenesis. Attune Pharmaceuticals is developing oral small molecules that will interfere with the MAC’s ability to locate C3b on the host cells for the prevention of PNH and other complement-mediated diseases.